211616Orig1s000

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

211616Orig1s000

RISK ASSESSMENT and RISK MITIGATION REVIEW(S) Division of Risk Management (DRM) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

Application Type NDA Application Number 211616 and 211617 PDUFA Goal Date February 21, 2020 OSE RCM # 2019-402 and 404

Reviewer Name Mei-Yean Chen, Pharm.D. Team Leader Naomi Boston, Pharm.D. Division Director Cynthia LaCivita, Pharm.D. Review Completion Date February 14, 2020 Subject Evaluation of Need for a REMS

Established Name Bempedoic acid and bempedoic acid/ezetimibe fixed dose combination (FDC) Trade Name Nexletol and Nexlizet Name of Applicant Esperion Theraputics, Inc. Therapeutic Class An adenosine triphosphate-citrate lyase inhibitor Formulation(s) Nexletol 180 mg tablet and Nexlizet (bempedoic acid 180 mg and ezetimibe 10 mg) Dosing Regimen Oral tablet once daily

Reference ID: 4561902 Table of Contents

EXECUTIVE SUMMARY ...... 3

1 Introduction ...... 3

2 Background ...... 3

2.1 Product Information ...... 3

2.2 Regulatory History...... 4

3 Therapeutic Context and Treatment Options ...... 4

3.1 Description of the Medical Condition ...... 4

3.2 Description of Current Treatment Options ...... 5

4 Benefit Assessment ...... 6

5 Risk Assessment & Safe-Use Conditions ...... 7

6 Expected Postmarket Use ...... 9

7 Risk Management Activities Proposed by the Applicant ...... 9

8 Discussion of Need for a REMS ...... 9

9 Conclusion & Recommendations ...... 10

10 Appendices ...... 10

10.1 References ...... 10

Reference ID: 4561902 EXECUTIVE SUMMARY This review evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity Nexletol/Nexlizet (bempedoic acid and bempedoic acid/ezetimibe) is necessary to ensure the benefits outweigh its risks. Esperion Therapeutics, Inc. submitted a New Drug Application (NDA 211616 and 211617) for bempedoic acid and bempedoic acid/ezetimibe with the proposed indication as an adjunct to diet and maximally tolerated statins therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of low-density lipoprotein cholesterol (LDL-C), with Limitations of Use: the effect of bempedoic acid on cardiovascular morbidity and mortality has not been determined. The risks associated with bempedoic acid include hyperuricemia and tendon rupture. The applicant did not submit a proposed REMS or risk management plan with this application.

Division of Risk Management (DRM) has determined that a REMS is not needed to ensure the benefits of bempedoic acid outweigh its risks. Statin therapy sometimes is not enough to achieve appropriate lowering of LDL-C. There remains a clear need to develop a new therapy that is both effective and safe in lowering LDL-C. Although bempedoic acid effect in reducing LDL-C is modest, with its safety profile, it provides an additional therapeutic option in patients who are not able to meet goals with current available therapies. If the product is approved, the recommendations for monitoring signs and symptoms of hyperuricemia and tendon rupture will be communicated in the Warnings and Precautions section of the labeling.

1. INTRODUCTION This review evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity (NME) bempedoic acid is necessary to ensure the benefits outweigh its risks. Esperion Therapeutics, Inc. (Esperion) submitted a New Drug Application (NDA) 211616 and 211617 for Nexletol and Nexlizet (bempedoic acid and bempedoic acid/ezetimibe) with the proposed indication as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFM) or established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of low-density lipoprotein cholesterol (LDL-C), with Limitations of Use: the effect of bempedoic acid on cardiovascular morbidity and mortality has not been determined. Nexlizet is a fixed dose combination (FDC), which contains bempedoic acid and ezetimibe (a cholesterol absorption inhibitor). This application is under review in the Division of Metabolism and Endocrinology Products (DMEP). The applicant did not submit a proposed REMS or risk management plan with this application.

2. BACKGROUND

2.1 PRODUCT INFORMATION Bempedoic Acid, a new molecular entity, is an adenosine triphosphate (ATP)-citrate lyase (ACL) inhibitor with the proposed indication as an adjunct to diet and maximally tolerated statins therapy for the treatment of adults with HeFM or established ASCVD who require additional lowering of LDL-C. As an

Reference ID: 4561902 ACL inhibitor, bempedoic acid acts upstream of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase to inhibit cholesterol biosynthesis in the liver and lower LDL-C in blood via upregulation of LDL receptors. Bempedoic acid is available as a 180 mg tablet with the proposed dosing as one tablet orally once daily. Bempedoic Acid is not currently approved in any jurisdiction.

2.2 REGULATORY HISTORY The following is a summary of the regulatory history for NDA 211616 and NDA 211617 relevant to this review:

x October 2009: Investigation New Drug (IND 106654) opened

x August 2015: End of phase 2 (EOP2) meeting

x September 2018: pre-NDA meeting

x 02/20/2019: NDA 211616 submission received

x 02/26/2019: NDA 211617 submission received

x 08/15/2019: A Post Mid-cycle meeting was held between the Agency and the Applicant via teleconference. The Agency informed the Applicant that based on the currently available data, there were no safety issues that require a REMS for bempepoic acid.

3 THERAPEUTIC CONTEXT AND TREATMENT OPTIONS

3.1 DESCRIPTION OF THE MEDICAL CONDITION Familial hypercholesterolemia (FH) is the most common autosomal dominant genetic disease. The clinical syndrome is characterized by extremely elevated levels of LDL-C and a propensity to early onset of ASCVD. The American Heart Association criteria for clinical diagnosis of FH is LDL-C>190 mg/dL and either a first degree relative with LCL-C>190 mg/dL or with known premature coronary heart disease (<55 years men; <60 years women)1. The prevalence of FM varies on definition used and the population studied. Few patients in a general medicine practice have FH using a definition that includes genetic testing. FH is an autosomal dominant disorder inherited with a gene dosing effect, in which homozygotes are more adversely affected than heterozygotes. Homozygous FH patients are rare and have an estimated prevalence of about 1:300,000 to 1:400,000. LDL-C level in patients with homozygous FM usually is higher than 500 mg/dL, while LDL-C level in patients with heterozygous FH (HeFH) is around 200-550 mg/dL. HeFH is estimated to occur in about 1 in 300 individuals in Europe and 1 in 200- 250 individuals in the United States (US).2 HeFH patients have high LDL-C levels from birth and a higher risk of premature coronary heart disease. Individuals with HeFH often demonstrate tendon xanthomata if untreated and have a family history of hypercholesterolemia. The prevalence of xanthomata increases with age, eventually occurring in 75% of patients with HeFH.

Reference ID: 4561902 Cardiovascular disease (CVD) is the leading cause of death in the United States (US)a affecting over one third of Americans b.3 Heart attack and stroke are usually caused by ASCVD. ASCVD develops because of a buildup of sticky cholesterol-rich plague. The plaque can harden and narrow the arteries as patients age. Elevated levels of LDL-C are associated with an increased risk of CVD events and lowering of LDL-C is associated with a reduction in these events. LDL-C level is an important modifiable risk factor for ASCVD. A meta-analysis of data from 14 randomized trials of statins demonstrated that lower LDL-C can significantly reduce the incidence of CVD in a wide range of patients4.

3.2 DESCRIPTION OF CURRENT TREATMENT OPTIONS The following is 2018 American Heart Association (AHA)/American Chest Association (ACA) treatment guideline for LDL-C reduction, in addition to adhere a healthy lifestyle5,

x Primary prevention: for adults who are free from ASCVD, use moderate-intensity statin

x Secondary prevention: for patients with ASCVD

o Not very high risk for recurrence: use high intensity statin +/- ezetimibe

o Very high risk for recurrence: use high intensity statin +/- ezetimibe +/- Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor

Table 1: Summary of Treatment Options and relevant to proposed indication and their adverse events

Drug name Route Warnings & Precautions

Statins: atorvastatin6, rosuvastatin7, Oral Myopathy, rhabdomyolysis, liver simvastatin8, pravastatin9, lovastatin10, enzyme abnormalities Fluvastatin11, pitavastatin12

Ezetimibe (ZETIA)13 Oral Myopathy, rhabdomyolysis (co- administered with statins), liver enzyme abnormalities

a Section 505-1 (a) of the FD&C Act: FDAAA factor (B): The seriousness of the disease or condition that is to be treated with the drug.

b Section 505-1 (a) of the FD&C Act: FDAAA factor (A): The estimated size of the population likely to use the drug involved.

Reference ID: 4561902 Alirocumab (PRALUENT) (a PCSK9 inhibitor)14 Subcutaneous Allergic reactions injection Evolocumab (REPATHA) (a PCSK9 inhibitor)15

Bile acid sequestrant Oral None, not absorbed and do not cause systemic side events, but associated Cholestyramine16 with gastrointestinal complaints such as Colestipol (COLESTID)17 constipation or obstruction, hypertriglyceridemia and pancreatitis, Colesevelam (WELCHOL)18 vit K or fat-soluble vitamin deficiency

4 BENEFIT ASSESSMENT There were 3,009 adult patients with HeFH or established ASCVD enrolled in two multi-center, randomized, double-blind, placebo-controlled trials to evaluate the efficacy of bempedoic acid. In both trials, the maximum LDL-C lowering effects occurred at week 4.20

Study 1 (NCT 02666664) was a multi-center, randomized, double-blind, placebo-controlled 52-week trial that evaluated safety and efficacy of bempedoic acid in patients with HeFH and/or ASCVD. At week 12, efficacy of bempedoic acid was evaluated. The trial included 2,230 patients randomized 2:1 to receive either bempedoic acid (n=1488) or placebo (n=742) as add-on to a maximally tolerated lipid lowering therapy. Patients were stratified by presence of HeFH and by baseline statin intensity. The mean age at baseline was 66 years (24-88 years), 61% were ш 65 years old, 27% women, 2% Hispanic, 96% White, 3% Black, and 1% Asian. Ninety-five percent of patients had established ASCVD, and 5% of patients had HeFH. Twenty-nine percent of patients had diabetes at baseline. The mean baseline LDL-C was 103.2 mg/dL. All patients were receiving statin therapy and 50% were receiving high-intensity statin therapy. The primary efficacy outcome measure was the percent change of LDL-C from baseline to week 12. The difference between bempedoic acid and placebo of LDL-C was -18.1% (95% confidence interval: -20.0%, -16.1%; p<0.001).

Study 2 (NCT 02991118) was a multi-center, randomized, double-blind, placebo-controlled, 52-week trial in patients with HeFH and/or ASCVD. The efficacy of bempedoic acid was evaluated at week 12. The trial included 779 patients randomized 2:1 to receive either bempedoic acid (n=522) or placebo (n=257) as add-on to maximally tolerated lipid lowering therapy. The mean age at baseline was 64 years (28-91 years), 51% were ш 65 years old, 36% women, 8% Hispanic, 94% white, 5% Black, and 1% Asian. Ninety- five percent of patients had established ASCVD, and 5% of patients had HeFH. The mean baseline LDL-C was 120.4 mg/dL. Ninety percent of patients were receiving statin therapy and 53% were receiving high- intensity statin therapy, and 0.3% were receiving PCSK9 inhibitors. The primary efficacy outcome measure was the percent change of LDL-C from baseline to week 12. The difference between bempedoic acid and placebo in mean percent change in LDL-C from baseline to week 12 was -17.4% (confidence interval -21%, -13.9%; p<0.001).

Reference ID: 4561902

The medical officer communicated at the midcycle meeting that there was a 17-18% additional LDL-C reduction at 12 weeks when bempedoic acid was added to maximally-tolerated statins and effects were sustained throughout treatment. Thirty percent of patients treated with bempedoic acid were able to achieve LDL-C <70 mg/dL. The medical reviewers conclude that even though the effect of bempedoic acid on LDL-C reduction is modest, the effect is clinically meaningful. Bempedoic acid provides an additional option to lower LDL-C in patients who are not able to meet goals with currently available therapy , such as maximally tolerated statins, ezetimibe or a PCSK9 inhibitor).19

5 RISK ASSESSMENT & SAFE-USE CONDITIONS The safety of bempedoic acid was evaluated in 2 placebo-controlled trials that included 2009 patients treated with bempedoic acid for 52 weeks. The mean age for bempedoic acid treated patients was 65 years, 34% were women, 94% were White, 4% Black, 1% Asian, and 1% other races. All patients received bempedoic acid 180 mg orally once daily plus maximally tolerated statin therapy alone or in combination with other lipid-lowering therapies. Ninety-seven percent of patients had clinical ASCVD and about 4% had a diagnosis of HeFH.

Study 1 and Study 2 randomized patients 2:1 to receive either bempedoic acid or placebo. There were 25 deaths (1.2%) reported in bempedoic acid arm compared to 8 deaths (0.8%) in placebo arm. Table 2 lists the causes of deaths. The medical officer concluded that “the overall imbalance in all-cause deaths between arms was primarily driven by malignancy-associated deaths that occurred > 30 days after drug discontinuation. Observed imbalances in deaths were most likely due to chance. Review of the safety database did not support an association between bempedoic acid exposure and mortality, CV harm, or malignancy risk.”19

Table 2 Deaths in safety population (studies 1 and 2), 52 weeks

deaths Bempedoic acid N=2009, n (%) Placebo N=999, n(%)

Total deaths 25 (1.2%) 8 (0.8%)

cardiovascular 12 (0.6%) 5 (0.5%)

Malignancy 9 (0.4%) 1 (0.1%)

Other 4 (0.2%) 2 (0.2%)

Within 30 days of last dose 14 (0.7%) 4 (0.4%)

Cardiovascular 11 (0.5%) 4 (0.4%)

Reference ID: 4561902 Malignancy 1 (0.0%) 1 (0.1%)

Other 3 (0.1%) 1 (0.1%)

Beyond 30 days of last dose 11 (0.5%) 4 (0.4%)

Cardiovascular 1 (0.0%) 2 (0.2%)

Malignancy 8 (0.4%) 0 (0.0%)

Other 1 (0.0%) 1 (0.1%)

The followings are the risksb associated with the use of bempedoic acid that will be included in warnings and precautions of the label.

5.1 HYPERURICEMIA Bempedoic acid inhibits renal tubular Organic Anion Transporter 2 (OAT2) and may increase blood uric acid levels. In clinical trials, hyperuricemia usually occurred within the first 4 weeks and persisted throughout therapy. Twenty-six percent of bempedoic acid treated patients with normal baseline uric acid (versus 9.5% placebo) reported hyperuricemia one or more times and 3.5% of patients experienced significant hyperuricemia reported as an adverse reaction (versus 1.1% placebo). The mean placebo- adjusted increase in uric acid compared to baseline was 0.8 mg/dL for patients in bempedoic acid arm after 12 weeks of therapy.

Gout may occur due to hyperuricemia. Gout was reported in 1.5% of patients in bempedoic acid arm compared to 0.4% of patients in placebo arm. The risk of developing gout was higher in patients with a history of gout, 11.2% in bempedoic acid arm versus 1.7% in placebo arm. Gout also occurred more frequently in patients treated with bempedoic acid (1.0%) than placebo (0.3%)who had no prior gout history.20

HCPs are advised to assess serum uric acid if clinically indicated. Signs and symptoms of hyperuricemia are to be monitored and start therapy with urate-lowering drugs as appropriate.

5.2 TENDON RUPTURE

b Section 505-1 (a) of the FD&C Act: FDAAA factor (E): The seriousness of any known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug.

Reference ID: 4561902 Increased risk of tendon rupture or injury associated with bempedoic acid was reported in clinical trials, 0.45% versus 0% of placebo arm. The most frequently involved were the bicep’s tendon, rotator cuff, and the Achilles tendon.5 Tendon rupture occurred within weeks to months of starting bempedoic acid. Patients who were over 60 years old, take corticosteroid or fluoroquinolone drugs, with renal failure, or with previous tendon disorders were to have increased risk of tendon rupture.20

If approved, Healthcare Providers (HCPs) are advised to discontinue bempedoic acid immediately if the patient experiences rupture of a tendon. If patients experience joint pain, swelling, or inflammation, consider discontinuing bempedoic acid. HCPs also need to advise patients to rest at the first sign of tendinitis or tendon rupture and to contact HCPs. If patients have a history of tendon disorders or tendon rupture, HCPs are advised to consider an alternative therapy.

6 EXPECTED POSTMARKET USE If approved, bempedoic acid will be used in both outpatient and inpatient settings. The likely prescribers will be primary care practitioners, internal medicine practitioners, and cardiologists.

7 RISK MANAGEMENT ACTIVITIES PROPOSED BY THE APPLICANT The Applicant did not propose any risk management activities for bempedoic acid beyond routine pharmacovigilance and labeling.

8 DISCUSSION OF NEED FOR A REMS The Clinical Reviewer recommends approval of bempedoic acid based on the efficacy and safety information currently available. DRM and DMEP agree that a REMS is not necessary to ensure the benefits of bempedoic acid outweigh its risks. When evaluating factors of a REMS is necessary to ensure that the benefits outweigh the risks for bempedoic acid, this reviewer considered the patient population, seriousness of the disease, expected benefit of the drug, seriousness of known or potential adverse events, and prescribing population.

HeFH is estimated to occur in about 1 in 200-250 individuals in US. Cardiovascular disease (CVD) is the leading cause of death in US and affects over one third of American. Elevated levels of LDL-C are associated with an increased risk of CVD events and lowering of LDL-C is associated with a reduction in CVD events. In the clinical trials of bempedoic acid, a there was a 17% additional LDL-C reduction which occurred at 12 weeks when added to maximally-tolerated statins, and the effect was sustained throughout treatment. Thirty percent of patients treated with bempedoic acid was able to achieve LDL-C <70 mg/dL.

The serious risks associated with bempedoic acid during clinical trials were tendon rupture and hyperuricemia. The recommendations for monitoring signs and symptoms of tendon rupture and hyperuricemia will be communicated in the Warnings and Precautions section of the labeling if the product is approved. Bempedoic acid will likely be prescribed by primary care practitioners, internal medicine practitioners, and cardiologists who are familiar with these risks and how to manage them.

Reference ID: 4561902 LDL-C reduction is generally considered a surrogate for lowering CVD risk. Use of LDL-C lowering as a surrogate is based on data from several large trials demonstrated CVD risk reduction with statins in primary and secondary prevention.21 However, statin therapy alone sometimes is not enough to achieve appropriate lowering of LDL-C. Therefore, many patients have LDL-C levels that are not at goal for their level of perceived risk. There remains a clear medical need to develop a new therapy that is both effective and safe in lowering LDL-C. Although bempedoic acid effect in reducing LDL-C is modest, with its safety profile, it provides an additional therapeutic option in high-risk patients who are not able to meet goals with current available therapies.

9 CONCLUSION & RECOMMENDATIONS Based on the clinical review, the benefit-risk profile is favorable therefore, a REMS is not necessary for bempedoic acid to ensure the benefits outweigh the risks. At the time of this review, evaluation of safety information and labeling was ongoing. Please notify DRM if new safety information becomes available that changes the benefit-risk profile; this recommendation can be reevaluated.

10 APPENDICES

10.1 REFERENCES

1 American College of Cardiology/American Heart Association: Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults, 2013

2 Rosenson RS , Durrington P. Familial hypercholesterolemia in adults: overview, www.uptodate.com, accessed 01/22/2010

3 Benjamin EJ, Blaha MJ, et al; American Heart Association statistics committee and stroke statistics subcommittee. Heart disease and stroke statistics-2017 update: a report from the American Heart Association Circulation. 2017; 135: e146-e603

4 Baigent C, Keech A, et al; Cholesterol treatment trialists (CTT) Collaborators. Efficacy and safety of cholesterol- lowering treatment: prospective meta-analysis of data from 90,056 participants in14 randomized trials of statins. Lancet. 2005; 366: 1267-1278.

5 2018 American Heart Association/American College of Cardiology guideline on the management of blood cholesterol: a report of the ACC/AHA task force on clinical practice guidelines. J Am Coll Cardiol 2018; Nov 10 6 Atorvastatin (Lipitor) prescribing information, Drugs@FDA, accessed 02/03/2020.

7 Rosuvastatin (Crestor) prescribing information, Drugs@FDA, accessed 02/11/2020.

8 Simvastatin prescribing information, Drugs@FDA, accessed 02/11/2020.

9 Pravastatin (Pravachol) prescribing information, Drugs@FDA, accessed 02/11/2020.

10 Lovastatin (Mevacor) prescribing information, Drugs@FDA, accessed 02/11/2020.

Reference ID: 4561902

11 Fluvastatin (Lescol) prescribing information, Drugs@FDA, accessed 02/11/2020

12 Pitavastain (Livalo) prescribing information, Drugs@FDA, accessed 02/11/2020

13 Ezetimibe (Zetia) prescribing information, Drugs@FDA, accessed 02/03/2020

14 Alirocumab (Praluent) prescribing information, Drugs@FDA, accessed 02/03/2020

15 Evolocumab (Repatha) prescribing information, Drugs@FDA, accessed 02/03/2020

16 Cholestyramine prescribing information, Drugs@FDA, accessed 02/11/2020

17 Colestipol (Colestid) prescribing information, Drugs@FDA, accessed 02/11/2020

18 Colesevelam (Welchol) prescribing information, Drugs@FDA, accessed 02/03/2020

19 Higginbotham L., Kettermann A. et al Draft Integrated Review of Nexletol (bempedoic acid) NDA 211616 on 02/04/2020

20 Bempedoic acid NDA 211616 draft prescribing information 02/05/2020

Reference ID: 4561902 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

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MEI-YEAN T CHEN 02/14/2020 01:42:49 PM

NAOMI S BOSTON 02/14/2020 01:50:00 PM

CYNTHIA L LACIVITA 02/14/2020 02:34:03 PM

Reference ID: 4561902